Process for hydroxychlorinating delta9(11)-steroids



United States Patent Ofiice 3,057,886 Patented Oct. 9, 1962 3,057,886PROCESS FOR HYDROXYCHLORINATING M -STEROIDS Josef Fried, Princeton,N.J., and Josef E. Herz, Mexico City, Mexico, assignors to OlinMathieson Chemical Corporation, New York, N.Y., a corporation ofVirginia No Drawing. Filed Dec. 10, 1958, Ser. No. 779,302 5 Claims.(Cl. 260397.45)

This application-in-part of our parent application, Serial No. 429,108,filed May 11, 1954, now abandoned.

This invention relates to a new process for synthesizing valuablesteroids.

An object of this invention is the provision of an advantageous processof introducing a 9a-chloro and 115- hydroxy radical into a M -steroid.

The process of this invention essentially comprises reacting a M-steroid with hypochlorous acid and recovering the product produced.

Steroids useful as starting materials in the practice of the process ofthis invention include the members of the A -androstene (including the A-etiocholene) and the A -pregnene (including the A -a1lopregnene)series; the preferred compounds belonging to the A pregnene series,which includes the A -pregnadiene and A -pregnatriene compounds. Thespecifically preferred compounds of the A -pregnene series are those ofthe general formula:

0 HzY the 1,2- and 4,5-positions being double-bonded or saturated,wherein R is H, R is -OH, or together R and R is :0 or a groupconvertible thereto by hydrolysis (such as a ketal group); Y is H,halogen, -OH, or OR'; and Z is either H or (a)-OH; R is an organicradical such as an acyl radical (acetyl, benzoyl, naphthoyl, etc.), analiphatic radical (methyl, ethyl, etc.) or an aralkyl radical (benZyl,phenethyl, etc.).

The resulting compounds have the general formula:

O HaY or carboxylic acids (including derivatives thereof), and include,inter alia, N-chloroacetamide.

The hypochlorous acid used for the conversion of the M -steroids to thecorresponding 9oc-ChlOI'O-1lj3-hY- droxy derivatives, may be employed assuch or may be formed in situ by interacting an N-chloro-amide or N-chloro-imide of a carboxylic acid (including derivatives thereof) withwater. Suitable N-chloro-amides and N- chloro-imides includeN-chloroacetamide (or N-chloroamides of other fatty acids),N-chlorosuccinimide (or other cyclic imides of amino fatty acids), andN,N-dichlorodimethylhydantoin. As previously stated, if such anN-chl0r0-am-ide or N-chloro-imide is employed, water must be present inthe reaction medium. The reaction medium preferably also includes aninert solvent for the steroid reactant. Representative of such solventsare the tertiary alcohols (such as tertiary butanol), ethers (such asacyclic ethers, e.g. diethyl ether and methyl isopropyl ether or cyclicethers, e.g. dioxane), and certain ketones.

Unless hypochlorous acid is used directly as the chlorinating agent, thereaction is preferably eifected in the presence of a relatively strongacid. Although any strong acid may be used, and acids such as sulfuricacid and nitric acid are operative, it is preferred to conduct thereaction in the presence of a strong acid whose anion possesses lownucleophilicity. By operating in this Way, losses due to the formationof undesired 11/3-esters are eliminated, and the final yield of thedesired product is increased. Suitable relatively strong acids includeperchloric acid, p-toluene sulfonic among others. It is noted that theuse of a relatively strong acid, such as perchloric acid, isadvantageous in the preparation of chlorinated IIB-hydroxy steroidsgenerally (e.g. from A steroids also), since it gives higher yields ofthe chloro llfl-hydroxy steroids because no by-product esters areformed.

In many instances when a M -steroid is treated in accordance with theprocess of this invention, a :,11/3- ,dichloro derivative is formed as aby-product, and this can be reduced by means of chromous chloride (orother reducing agent capable of reducing compounds possessing (vicinalchlorine atoms, e.g. zinc and acetic acid, and Raney nickel) toregenerate the M -steroid, and this latter can then be separated fromthe desired 9a-chlorollfi-oxygenated steroid. This reduction may becarried out in situ or in a separate operation.

If the reaction is conducted in an aqueous medium, an ll/i-hydroxysteroid is produced. To obtain an llfi-organo-oxy derivative, ananhydrous alcoholic or acid solution is used. If methanol is substitutedfor water, an llfl-methoxy compound is produced. If acetic acid issubstituted for water, an 11 [R-acetoxy compound is formed.

The following examples are illustrative of the invention:

EXAMPLE 1 9a-Chl0rohydrocortisone Acetate (9u-Chl0r0-A -Preg'nene11,8,17a,21-Tri0l-3,20-Di0ne ZJ-Acetate) From A4,9(11)Pregnadiene-1.7a,21 -Di0l-3,20-Di0ne 21-Acetate 246 mg. of finelypulverized A -pregnadiene :,21- diol-3,20-dione 2l-acetate is dissolvedin 50 m1. of hot dioxane and after adding 5 ml. of water, the solutionis rapidly cooled to room temperature while agitating. To the resultingsuspension is added 268 mg. of N,N-dichlorodimethyl-hydantoin and 5 ml.of 1 N perchloric acid, and the reaction is allowed to proceed at roomtemperature for two and one-half hours. ExcessN,N-dichlorodimethylhydantoin is then destroyed by the addition ofdilute aqueous sodium sulfite. 50 ml. of chloroform is added, and thesmall aqueous phase floating on top is.

separated off. The chloroform-dioxane phase is washed with dilute sodiumbicarbonate and with water and dried over sodium sulfate. Removal of thesolvents in vacuo leaves a readily crystallizing residue (about 330 mg).A small portion of the residue is recrystallized for analysis fromacetone, M.P. about 241 C. (dec.).

Analysis.Calcd. for C H O Cl (455.36): C, 60.66; H, 6.19; Cl, 15.57.Found (approximately): C, 60.88; H, 6.60; Cl, 15.41.

The above compound represents 9a,11fi-dichloro-Apregnene-l7a,2l-diol-3,20-dione 21 acetate. The total mixture obtainedabove is dissolved in 5 ml. dioxane and treated at room temperature with2 ml. of an aqueous solution of chromous chloride [prepared as describedin the J. Am. Chem. Soc., 72, 4080 (1950)]. After 30 minutes thereaction mixture is aerated to oxidize the remaining chromous chlorideto chromic chloride and 20 ml. of chloroform is added. After separationof the layers, the chloroform-dioxane extract is washed with water,dilute sodium bicarbonate, and again with water and finally dried oversodium sulfate. Removal of the solvents in vacuo leaves a residue (about286 mg.) which crystallizes spontaneously. Since this product is amixture, it is chromatographed on 6 g. of silica gel. Elution withchloroform yields A -pregnadiene-17a,2l-diol 3,2-dione Zl acetate (about1:10 mg.) which after recrystallization from acetone melts at about234-236 C. A mixture melting point with an authentic sample of thatsubstance shows no depression. Subsequent elution of the column withacetone in chloroform affords 9a-chloro-hydrocortisone acetate (about100 mg.) which after crystallization, first from acetone-hexane andfinally from acetone, melts at about 202 C. (dec.). Infrared comparisonwith an authentic sample of 9a-chlorohydrocortisone acetate shows thetwo to be identical.

EXAMPLE 2 Reaction of A -Pregnadiene-1 7a,21-Di0l-3,20-Di0l1e 21-AcetaleWith Hypochlorous Acid To a suspension of 400 mg. of A -pregnadiene-l7a,2l-diol-3,20-dione 21-acetate in 40 ml. of dioxane and 4 ml. of Water isadded at room temperature 2.5 ml. of an 0.61 N aqueous solution ofhypochlorous acid (prepared by saturating a solution of sodiumbicarbonate with chlorine at 0 and adjusting the pH of the resultingsolution with sodium hydroxide to 6.7). The suspension clears within 2minutes, and minutes later excess hypochlorous acid is destroyed by theaddition of sodium sulfite solution. 150 ml. of chloroform is added, thephases are separated and the chloroform solution washed with water.After drying over sodium sulfate the solvent is removed in vacuo. Thecrystalline residue after several recrystallizations from acetone hasthe following properties: M.P. about 24324-4 (dec.); +164 (c. 107 inCHCl A553, 238 mp. (e=15,600)

Analysis.-Calcd. for C H O Cl C, 60.3; H, 6.62; Cl, 15.55. Found: C,60.36; H, 6.68; Cl, 13.38.

To obtain 9a-chlorohydrocortisone acetate, the total reaction product istreated with chromous chloride and the resulting mixture of A-pregnadiene-l7u,21-diol- 3,20-dione Ill-acetate and9a-chlorohydrocortisone acetate separated by chromatography as describedin Example 1.

EXAMPLE3 9a-Chloro-115,17a-Dilzydroxyprogesterone From A Pregnadiene-J7a-oI-3,20-Dione 110 mg. of n -pregnadiene-17a-ol-3,20-dione isdissolved in 20 ml. of dioxane and 2 ml. of water is added. To theresulting solution is added 100 mg. of N,N-dichlorodimethylhydantoin andthe mixture is allowed to stand at room temperature for 30 minutes.Dilute aqueous sodium sulfite solution is added to destroy residualN,N-dichloro-dimethy1 hydantoin and the EXAMPLE 4 9a-ChIor0-IIfi-Hydroxyprogesterone From 13 Pregrzadiene-S .ZO-Dimw A solution of103 mg. of A -pregnadiene-3,20-dione in 20 ml. of dioxane and 2 ml. ofwater is treated with mg. of N,N-dichlorodimethylhydantoin and 1 ml. ofl N perchloric acid as described above. The resulting crystallineresidue (about mg.) is dissolved in 4 ml. of acetone and treated with 1m1. of a chromous chloride solution as described in Example 1. Thework-up yielded about 104 mg. of amorphous material which is dissolvedin 0.5 ml. of chloroform and 4 ml. of benzene and chromatographed on 2g. of silica gel. Elution of the column with chloroform benzene 1:8 (230ml.) affords about 35 mg. of A -pregnadiene3,2O-dione. Subsequentelution of the column with benzene chloroform 1:1 (300 ml.) furnishesabout 43 mg. of crude 9u-chloro-11[ihydroxyprogesterone, which aftercrystallization from acetone-hexane has the following properties: M.P.approximately 205 C. (dec.); +199 (0., 0.59 in chloroform). There is nodepression in melting point when this material is mixed with anauthentic sample of 9a chloro-l 1 fi-hydroxyprogesterone.

The above two reactions could be combined into a single work-up byadding the chromous chloride solution directly to the initial reactionmixture after the destruction of excess N,N-dichlorodimethylhydantoinwith sodium sulfite, as described in the following example:

EXAMPLE 5 9a-Cl1loro-Ilfl-Hydroxyprogesterone From APregnadiene-3,20-Dione A solution of 103 mg. of A-pregnadiene-3,20-dione in 20 ml. of dioxane and 2 ml. of water istreated with 100 mg. of N,N-dichlorodimethylhydantoin and 1 ml. of 1 Nperchloric acid as in Example 4. Excess N,N-dichlorodimethylhydantoin isthen destroyed by the addition of dilute aqueous sodium sulfite. Themixture is diluted with 30 ml. of chloroform which causes separationinto two layers. The chloroform-dioxane phase is separated off, washedwith water, sodium bicarbonate, and again with water; it is freed fromchloroform by vacuum concentration and treated with 2 ml. of a chromouschloride solution as described in Example 1. The work-up yields about 45mg. of 9a-chloro-llfl-hydroxyprogesterone.

EXAMPLE 6 9a-Chlorocorticosterone Actate From A -Pregnadflene-21-0l-3,20-Di0ne 21Acetalc Following the process of Example 1, butsubstituting A -pregnadiene 21 ol 3,20 dione ZI-acetate for A-pregnadiene-17a,21-diol-3,20-dione 2l-acetate, the corresponding9ot-chlorocorticosterone acetate is produced.

EXAMPLE 7 Following the process of Example 1, but substituting A-pregnadiene1701,2l-diol-3,20-dione for the corresponding 2l-acetate,the compound 9ot-chloro-A -pregnene-11fi,17a,21 triol 3,20-dione(9a-chlorohydrocortiacne) is produced.

EXAMPLE 8 9a-Chl0r0prednis0lone Acetate From A -Pregnatriene-J 711,21-Di0l-3,20-Di0ne 21-Acetate Following the procedure of Example 1, butsubstituting 240 mg. of A -pregnatriene-17u,21-di0l-3,20- dione21-acetate for the diene in the example, there is obtained9a-chloroprednisolone acetate.

The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. The process for converting a A -steroid to a corresponding9a-chloro-11/3-hydroXy steroid which comprises reacting said steroidwith N,N-dichlorodimethylhydantoin in the presence of Water and a strongacid whose anion possesses low nucleophilicity, and recovering said9a-chloro-1/1/3-hydroxy steroid.

2. The process for converting A -pregnadiene-17aol-3,20-dione to9a-chloro-1l5,l7ot-dihydroxyprogesterone which comprises reacting saidpregnadiene with N,N-dichlorodimethylhydantoin in the presence of waterand a strong acid whose anion possesses low nucleophilicity andrecovering 9u-chloro-11/3,l7a-dihydroxyprogesterone.

3. The process for converting A -pregnadiene-3,20- dione to9u-chloro-1lfl-hydroxyprogesterone which comprises reacting saidpregnadiene with N,N-dichlorodimethylhydantoin in the presence of waterand a strong acid whose anion possesses low nucleophilicity,dechlorinating a polychlorinated by-product formed thereby, andrecovering 9a-chlor0-1 lfi-hydroxyprogesterone.

4. The process for converting a A -pregnene of the general formula:

C HzY wherein the carbon atoms in the 1,2 and 4,5 positions are joinedby bonds selected from the group consisting of single and double bonds,R is hydrogen, R is hydroxyl, and when taken together R and R isselected from the ground consisting of oxo and a group convertiblethereto by hydrolysis; Y is selected from the group consisting ofhydrogen, hydroxy, halogen and the acyloxy radical of a hydrocarboncarboxylic acid of less than ten carbon atoms; and Z is selected fromthe group consisting of hydrogen and a-hydroxy, to the corresponding9u-Ch1010- llfi-hydroxy derivatives, which comprises reacting saidunsaturated pregnene in the presence of water with N,N-dichlorodirnethylhydantoin in the presence of a strong acid whose anionpossesses 10W nucleophilicity, and recovering the 9a-chloro-11fl-hydroxyderivative.

5. The process for converting a 21-ester of Apregnadiene-l7a,2l-diol-3,20-dione and a hydrocarbon carboxylic acid ofless than ten carbon atoms to the corresponding 21-ester of9a-chlorohydrocortisone, which comprises reacting said pregnadiene inthe presence of perchloric acid with N,N-dichlorodimethylhydantoin inthe presence of water, dechlorinating a polychlorinated by-productformed thereby by treatment with chromous chloride, and recovering the9a-chlorohydrocortisone produced.

References Cited in the file of this patent UNITED STATES PATENTS2,707,190 Farrar Apr. 26, 1955 2,751,402 Schneider June 19, 19562,838,501 Campbell et a1 June 10, 1958 2,852,511 Fried Sept. 16, 1958OTHER REFERENCES Rosenkranz et al.: I. Am. Chem. Soc., vol. 72 (1950),page 4080.

Fried et al.: J. Am. Chem. 800., volume 75 (May 5, 1953), pages 2273 and2274,

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 O57886 October 9 1962 Josef Fried et a1 It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 1, line 11, for "application-impart" read application is acontinuati0n-inpart column l line 61,, for *Actate'fl in italics readAcetate in italics,

Signed and sealed this 22nd day of October 1963 (SEAL) Attestz' EDWIN L5REYNOLDS i I ERNEST Wu SWIDER I l Attesting Officer AC ting Commissionerof Patents

1. THE PROCESS FOR CONVERTING A $9(11)-STEROID TO A CORRESPONDING9A-CHLORO-11B-HYDROXY STEROID WHICH COMPRISES REACTING SAID STEROID WITHN,N-DICHLORODIMETHYLHYDANTOIN IN THE PRESENCE OF WATER AND A STRONG ACIDWHOSE ANION POSSESSES LOW NUCLEOPHILICITY, AND RECOVERING SAID9A-CHLORO-11B-HYDROXY STEROID.